N-methoxy-N-acylnitrenium ions: Application to the formal synthesis of (±)-desmethylamino FR901483

Article abstract of DOI:10.1021/ol0161514

(matrix presented) The formal synthesis of (±)-desmethylamino FR901483 (2) is described. Construction of the unique azatricyclic skeleton of 2 was accomplished by a sequence which involved (i) preparation of dienone 7 by an N-methoxy-N-acylnitrenium ion-i

Full text of DOI:10.1021/ol0161514

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2353-2356
N-Methoxy-N-acylnitrenium Ions:
Application to the Formal Synthesis of
(±)-Desmethylamino FR901483
Duncan J. Wardrop* and Wenming Zhang
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
wardropd@uic.edu
Received May 22, 2001
ABSTRACT
The formal synthesis of (±)-desmethylamino FR901483 (2) is described. Construction of the unique azatricyclic skeleton of 2 was accomplished
by a sequence which involved (i) preparation of dienone 7 by an N-methoxy-N-acylnitrenium ion-induced spirocyclization, (ii) formation of
2-azabicyclo[3.3.1]nonane 5 by the 6-(π-exo)-exo-trig radical cyclization of 1,7-enyne 6, and (iii) installation of the C-5 p-methoxybenzyl side
chain by Lewis acid-mediated alkylation of silyl enol ether 18.
The immunosuppressive natural products cyclosporin A and
FK506 have played a key role in the advancement of
transplant surgery and the treatment of autoimmune dis-
eases.1,2 However, these drugs have serious side effects3 and
as a result, there is a need to develop less toxic immuno-
suppressants that selectively inhibit organ rejection but leave
the native immune system able to respond to viral, fungal,
and tumor antigens. FR901483 (1) (Figure 1), a secondary
metabolite of Cladobotryium sp. No. 11231 isolated by a
group at Fujisawa, is a potent immunosuppressant which
significantly increases the survival time of grafts in the rat
allograft model.4,5 This intriguing alkaloid contains 2-aza-
bicyclo[3.3.1]nonane and pyrrolidine rings spiro-fused to
form a azatricyclic skeleton previously unprecedented in
Nature. It is not surprising then that synthetic interest in this
target has been considerable. To date, syntheses of 1 have
been reported by Snider,6a,b Sorenson,6c Ciufolini,6d and, most
recently, by Funk.6e In addition, a number of approaches to
the azatricyclic core of 1 have also been published.7 We
(1) Cyclosporin A; Borel, J. F., Ed.; Elsevier Biochemical Press:
Amsterdam, 1982.
(2) Schreiber, S. L. Cell 1992, 70, 365-368.
(3) (a) Myers, B. D.; Ross, J.; Newton, L.; Leutscher, J.; Perlroth, M. N.
Engl. J. Med. 1984, 311, 699-705. (b) Shapiro, R.; Jordan, M.; Fung, J.;
McCauley, J.; Johnston, J.; Iwaki, Y.; Tzakis, A.; Hakala, T.; Todo, S.;
Starzl, T. E. Transplant Proc. 1991, 23, 920-923.
(4) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37-44.
(5) Although the mode of action of 1 remains to be elucidated, it has
been suggested that FR901483 may interfere with the biosynthesis of
purine: refs 3 and 6e.
Figure 1. 1-Azaspiro[4.5]decane alkaloids: FR901483 (1), des-
methylamino FR901483 (2), and TAN1251A (3).
10.1021/ol0161514 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/22/2001

recently reported the synthesis of (+)-TAN1251A (3),8 which
shares a common 1-azaspiro[4.5]decane skeleton with
FR901483, utlizing the Ar1-5 spirocyclization of N-methoxyl-
N-acylnitrenium ion 8 (Scheme 1).9 Having completed the
the facial dissymmetry of 5 to install the C-5 p-methoxy-
benzyl side chain and C-6 stereocenter at a late stage in the
synthesis.15 The cyclization precursor 6 could be obtained
from dienone 7 which, in turn, would be accessible through
the spirocyclization of the N-acyl-N-methoxynitrenium ion
8, as reported in our synthesis of TAN1251A.9
Our route to 4 commenced from commercially available
9 which was coupled with methoxylamine hydrochloride
(DCC, Et3N) to provide 10 in excellent yield (Scheme 2).
Scheme 1. Retrosynthetic Analysis for Desmethylamino
FR901483 (2)
Scheme 2a
first leg of our divergent study, we now report the application
of this chemistry to the formal synthesis of (()-desmethy-
lamino FR901483 (2).
a Reagents and conditions: (a) MeONH2‚HCl, DCC, Et3N,
CH2Cl2, 0 °C f rt, 21 h; (b) i. PhI(OCOCF3)2, CH2Cl2, MeOH, 0
°C, 15 s; ii. NaHCO3, H2O, 0 °C, 5 min; (c) H2 (1 atm), Pd/C,
EtOAc, rt, 20 h; (d) (CH2OH)2, PPTS, PhH, reflux, 3.5 h; (e) i.
Na, NH3, THF, -78 °C, 30 min; ii. NH4Cl, 0 °C f rt, 3 h.
As indicated in Scheme 1, the ultimate goal of the study
reported here was tricycle 4, an advanced intermediate in
Snider’s pioneering synthesis of desmethylamino FR901483
(2).6a We viewed 4 as being accessible from tricycle 5
through a sequence involving alkylation of the corresponding
C-6 ketone. In common with other groups,6 we deemed
formation of the C-6/C-7 bond as the most convenient
strategy to access the 2-azabicyclo[3.3.1]nonane ring sys-
tem.10 However, while all reported syntheses of 1 have
achieved this bond formation through internal aldol reactions
(or variants thereof), we were somewhat concerned about
both the issue of C-6 stereocontrol and the likelihood of
epimerization at the adjoining benzylic stereocenter. To side
step these issues, we opted to prepare 5 from enol ether 6
via a 6-(π-exo)-exo-trig radical cyclization,11-13 mediated by
the addition of a stannyl radical,14 and then capitalize on
Treatment of 10 with bis(trifluoroacetoxy)iodobenzene re-
sulted in rapid spirocylization to furnish 7. While this
material proved prone to decomposition under acidic condi-
tions, by reducing the reaction time to a mere 15 s and
immediately quenching the reaction with aqueous NaHCO3
we were able to prepare multigram quantities of 7 in
reasonable yield. Dienone hydrogenation (H2, Pd/C), protec-
tion of the resulting ketone as the 1,3-dioxolane acetal, and
reductive cleavage of the N-methoxyl amide under Birch
conditions16 now provided pyrrolidone 11. N-Alkylation with
propargyl bromide17 and acetal hydrolysis furnished 12 which
(6) (a) Snider, B. B.; Lin, H.; Foxman, B. M. J. Org. Chem. 1998, 63,
6442-6443. (b) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778-
7786. (c) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int. Ed.
2000, 39, 4593-4596. (d) Ousmer, M.; Braun, N. A.; Ciufolini, M. A. Org.
Lett. 2001, 3, 765-767. (e) Funk, R. L.; Maeng, J. H. Org. Lett. 2001, 3,
1125-1128.
(7) (a) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem. 1997,
62, 8280-8281. (b) Quirante, J.; Escolano, C.; Diaba, F.; Bonjoch, J. J.
Chem. Soc., Perkin Trans. 1 1999, 1157-1162. (c) Sole, D.; Peidro, E.;
Bonjoch, J. Org. Lett. 2000, 2, 2225-2228. (d) Suzuki, H.; Yamazaki, N.;
Kibayashi, C. Tetrahedron Lett. 2001, 42, 3013-3015. (e) Brummond, K.;
Lu, J. Org. Lett. 2001, 3, 1347-1349.
(8) Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. PCT Int. Appl.
WO 91 13,887,1991; Chem. Abstr. 1992, 116, 39780t.
(9) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053-1056.
(10) For a review of earlier synthetic studies on the 2-diazabicyclo[3.3.1]-
nonane ring system, see: Bosch, J.; Bonjoch, J. Heterocycles 1980, 14,
505-529.
(11) For a leading reference to the application of 6-exo-trig radical
cyclizations in synthesis, see: Pedrosa, R.; Andre´s, C.; Duque-Soladana,
J. P.; Roso´n, C. D. Tetrahedron: Asymmetry 2000, 11, 2809-2821 and
references therein.
(12) For reports of 6-exo-trig cyclizations involving the addition of
radicals to the distal terminus of enol and thioether acceptors, see: (a)
Marco-Contelles, J.; Sa´nchez, B. J. Org. Chem. 1993, 58, 4293-4297. (b)
Batty, D.; Crich, D.; Fortt, S. M. J. Chem. Soc., Chem. Commun. 1989,
1366-1368. (c) Reference 7b.
(13) The 6-endo-trig cyclization of alkenyl radicals with silyl enol ether
acceptors has also been reported: Urabe, H.; Kuwajima, I. Tetrahedron
Lett. 1986, 27, 1355-1358.
(14) Stork, G.; Mook, R. J. Am. Chem. Soc. 1987, 109, 2829-2831.
(15) While this work was in progress Bonjoch and co-workers reported
a route to 2-azabicyclo[3.3.1]nonanes involving the 6-exo-trig cyclization
of 1-(carbamoyl)dichloromethyl radicals with silyl enol ethers: ref 7b.
(16) Davies, S. G.; Smyth, G. D. J. Chem. Soc., Perkin Trans. 1 1996,
2467-2477.
2354
Org. Lett., Vol. 3, No. 15, 2001

was converted to the corresponding trimethylsilyl enol ether
using trimethylsilyl iodide and (TMS)2NH (Scheme 3).18 This
tion to take place,20 16 is unable to cyclize. However 16
does meet the stereoelectronic requirements for 1,5-transfer
of the adjacent allylic hydrogen atom.21,22 The allylic radical
thus generated then undergoes diastereoselective cyclization
with the pendant vinyl stannane to form 13.23
Having established a protocol for formation of the
2-azabicyclo[3.3.1]nonane core of the target, we now pro-
ceeded to install the C-5 side chain. Protection of the
hydroxyl group of 5 as the benzyl ether and oxidative
cleavage of the exo-olefin gave ketone 17 (Scheme 4). Our
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) i. NaH, DMF, 0 °C, 3 h; ii.
BrCH2CtCH, 0 °C, 4 h; (b) 0.5 M HCl, acetone, 50 °C, 18 h; (c)
i. (Me3Si)2NH, CH2Cl2, rt, 30 min; ii. Me3SiI, -20 °C, 10 min
then rt, 3 h; (d) i. Bu3SnH (1.2 equiv), AIBN (0.1 equiv), PhH
(0.08 M), 80 °C, 4.5 h; ii. MeOH, HCl, H2O, rt, 2 h.
1
material was found to be of sufficient purity, by H NMR
spectroscopy, to allow direct submission to the radical
cyclization.
After screening a number of radical initiators and solvents,
we found that slow addition of a mixture of n-Bu3SnH and
AIBN in benzene to a solution of 6 in the same solvent at
reflux over 4.5 h followed by protodestannylation (HCl,
MeOH) of the crude reaction mixture gave the desired
cyclization product 5 together with tricycle 1319 and a small
amount of reduction product 14. Both 5 and 13 where
isolated as single diastereomers whose relative stereochem-
istries were determined through a combination of COSY,
NOESY, and HMQC experiments.
Interestingly, the outcome of the cyclization reaction
displayed a significant temperature dependency, e.g., use of
toluene as the reaction medium favored the translocation-
cyclization pathway and led to the formation of 13 and 5 in
a 2:1 ratio. As illustrated in Figure 2, we have rationalized
these observations in terms of conformers 15 and 16. While
15 can adopt the geometry necessary for 6-exo-trig cycliza-
a Reagents and conditions: (a) BnBr, NaH, Bu4NBr, DMF, rt, 6
h; (b) i. OsO4, py, tert-BuOH, THF, H2O, 30 min, rt; ii. NaIO4, 6
h, rt; (c) i. KHMDS, THF, -50 °C, 15 min; ii. Et3SiCl, -50 °C,
40 min; (d) 18, p-MeOBnBr, ZnCl2‚Et2O, Et2O, -78 °C f -25
°C, 16 h; (e) SmI2, THF, H2O, rt, 5 min; (f) LiAlH4, THF, -78 °C
f rt, 22 h; (g) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 3 h; (h) see ref
6a.
initial attempts to alkylate various metal enolates of 17 with
p-methoxybenzyl bromide were unsuccessful, with low yields
of 19 and significant amounts of the dialkylated product and
starting material being obtained. Encouragingly, we found
(17) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802-4809.
(18) Miller, R. D.; McKean, D. R. Synthesis 1979, 730-732.
(19) This pyrrolizidine-based tricyclic ring system is present in the
remarkable decacyclic alkaloid myrmicarin 663: Schro¨der, F.; Sinnwell,
V.; Baumann, H.; Kaib, M.; Francke, W. Angew. Chem., Int. Ed. Engl.
1997, 36, 77-80.
(20) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines and Synthetic Applications; VCH: Wein-
heim, 1996; pp 77-82.
(21) (a) Lathbury, D. C.; Parsons, P. J.; Pinto, I. J. Chem. Soc., Chem.
Commun. 1988, 81-82. (b) For an informative review of the application
of radical translocation-cyclization reactions in synthesis, see: Robertson,
J.; Pillai, J.; Lush, R. K. Chem. Soc. ReV. 2001, 30, 94-103.
Figure 2. Competing radical pathways: 6-(π-exo)-exo-trig cy-
clization vs 1,5-hydrogen atom transfer/5-(π-exo-)-exo-trig cycliza-
tion.
Org. Lett., Vol. 3, No. 15, 2001
2355

that this obstacle could be overcome by Lewis acid-mediated
R-alkylation of enol ether 18.24 Thus, sequential treatment
of 17 with KHMDS and Et3SiCl furnished 18 which, after
isolation, was treated with p-methoxybenzyl bromide and
ZnCl2 to give 19 as a single stereoisomer. Reduction of the
C-6 ketone with samarium diiodide now cleanly generated
the desired exo-alcohol 20 in good yield.25 The relative
stereochemistry of 20 was confirmed by a NOESY experi-
ment which revealed correlations between H-6 and H-7 and
the axially positioned proton at C-9.
Figure 3. Selected NOESY correlations for 2-azabicyclo[3.3.1]-
nonane 4.
Reduction of lactam 20 with LiAlH4 in THF now gave
the desired pyrrolidine 21 (28%) and, rather unexpectedly,
diol 4 (39%), the product of benzyl ether cleavage.26 Catalytic
hydrogenolysis of 21 over Pd(OH)2/C now proceeded
smoothly to give 4 in 99% yield. The combined overall yield
for the conversion of 20 to 21 was 66%. As illustrated in
Figure 3, the relative stereochemistry of 4 was confirmed
by measurement of NOESY correlations. In addition, a
comparison of the spectroscopic data collected for 4 with
that reported by Snider indicated a close match.6a
In summary, we have developed a synthetic route to 4
which Snider has previously carried to 2 in six steps with
an overall yield of 38%.6a Accordingly, the work reported
here represents a formal synthesis of desmethylamino
FR901483 (2). Efforts to complete the asymmetric synthesis
of FR901483 (1) are now underway and will be reported in
due course.
Acknowledgment. We wish to thank the University of
Illinois at Chicago, the National Institutes of Health
(GM59157-01), and the UIC Campus Research Board for
financial support. W.Z. thanks the University of Illinois for
a University Graduate Fellowship.
(22) Huang, X. L.; Dannenberg, J. J. J. Org. Chem. 1991, 56, 5421-
5424.
(23) For a recent example of a 1,5-hydrogen atom transfer-cyclization
process involving a vinyl stannane, see: Toyota, M.; Yokota, M.; Ihara,
M. J. Am. Chem. Soc. 2001, 123, 1856-1861.
(24) For a review of Lewis acid-mediated R-alkylations, see: Reetz, M.
T. Angew. Chem., Int. Ed. Engl. 1982, 21, 96-108.
Supporting Information Available: Full experimental
procedures and spectral data for compounds 4-21. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) (a) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc.
1987, 109, 6187-6189. (b) Molander, G. A. Org. React. 1994, 46, 211-
367.
(26) For a report of the cleavage of a benzyl ether under similar
conditions, see: Kutney, J. P.; Abdurahman, N.; Glestsos, C.; Le Quesne,
P.; Piers, E.; Vlattas, I. J. Am. Chem. Soc. 1970, 92, 1727-1735.
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